Recently in Neuropsychiatry Category

The Alzheimer's Association has a new report on the large and growing effect of Alzheimer disease and other dementias on Americans. Here's the distillation:

• AD is the most common cause of dementia, affecting 5.3 million Americans (1.7% of the current US population). The vast majority (96%) of those affected are older than 64 years of age.
• Dementia affects women preferentially because they live longer, on average, than men. (Advancing age is the biggest risk factor for AD.)
• In 2006, AD was the 7th leading cause of death among all Americans. In those older than 64 years of age, AD was the 5th most likely cause of death.
• Next year, the first baby boomers will turn 65. In 30 years, all of the estimated 70 million baby boomers will be older than 65. The Association estimates that there will be 1 million new cases of AD by the year 2050.
• People with AD and other types of dementia need a lot of health care, including long-term and hospice care. In 2010, care costs for people with dementia will reach $172 billion. Medicare costs for people with dementia are nearly 3 times higher than those for the nondemented elderly. Medicaid costs are nearly 9 times higher. (Blogger's note: I suspect this is the result of Medicaid-funded nursing home care.)
• Older African Americans and Hispanics are about 2 and 1.5 times more likely, respectively, to have AD and other types of dementia than older whites.* Reasons for the higher risk of AD among these minorities include a greater prevalence of known risk factors for dementia, like hypertension, diabetes, and lower education and income levels. (Ethnically dependent genetic risks have not been identified.) Despite the higher risk of dementia among African Americans and Hispanics, the diagnosis is more likely to be delayed in affected minority patients. Delays in diagnosis mean missed opportunities for treatment, which is more likely to be effective in the early stages of AD.
• Last year, nearly 11 million family members or other uncompensated persons provided 12.5 billion hours of care for people with dementia. Unpaid care was assessed at $144 billion, which is more than the US government (ie, Medicare and Medicaid) spends on people with dementia. Costs of giving care are also measured in emotional and physical stress, declining caregiver health, and lost employment-related productivity. 

* This is the lead of today's press release from the Alzheimer's Association.

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.

The most common, identifiable form of pediatric epilepsy, absence seizures (formerly known as petit mal seizures) were first described in the early 18th century by (you guessed it) a French guy. Effective and relatively safe pharmacologic treatment for the condition has been available since 1960, when ethosuximide (Zarontin) was introduced by Parke-Davis (now a subsidiary of Pfizer, like just about every other drug company).

Absence seizures are also responsive to valproic acid (aka Depakene or Depakote; Abbott), which was FDA approved for treatment of the disorder in 1978, and lamotrigine (Lamictal; GSK), which has been studied for the treatment of absence seizures since at least the late 1990s.*

Despite our extensive clinical experience with these drugs, it was unknown which provided the best empirical therapy for absence epilepsy. In fact, Glauser and other neurologists at the University of Cincinnati concluded in 2006 that it was "impossible to develop an evidence-based guideline" for the initial, monotherapy treatment of generalized seizures and specifically those in children, because of the "alarming lack of well-designed, properly conducted" randomized, controlled trials. This finding evidently prompted Glauser and his colleagues to conduct a randomized, double-blind multicenter trial of the 3 drugs in children with newly diagnosed absence seizures—the results of which are available in today's issue of the NEJM.

Among 453 children with new-onset absence epilepsy, Glauser et al found that ethosuximide or valproic acid were significantly more likely to result in a primary composite outcome of seizure control and tolerability (~50%-60% of patients) than lamotrigine (~30% of patients) after 4 months. Attentional deficit, a secondary outcome measure, was significantly more likely with valproic acid than ethosuximide (49% vs 33%).

Commenting at MedPage Today, Glauser said, "[E]thosuximide gave the child the best chance to get the combination of seizure control without side effects or [adverse] effects on attention."

So ethosuximide, it is; then valproic acid; then lamotrigine.

* Although lamotrigine is not FDA approved for the treatment of absence seizures specifically.

The characteristic 3-per-second spike-and-wave EEG pattern of absence epilepsy from An Introduction to Epilepsy.

Someday I'm going to learn to capitalize on the overblown expectations and inevitable letdown of AD drug development.

Dimebon (latrepirdine), the nonselective antihistamine that Pfizer shelled out millions for, failed to improve cognition or global functioning in a placebo-controlled phase 3 study of patients with mild-moderate Alzheimer disease. The disappointing results were distributed today by way of press release from the drug's codevelopers, Medivation and Pfizer.

In a double-blind study of 598 individuals with AD in North America, Europe, or South America, Dimebon 20 mg tid was no better than placebo for improving or delaying declines in cognition (as measured with the ADAS-cog) or global functioning (as measured with the CIBIC-plus) at 6 months. Measures of secondary endpoints (eg, activities of daily living) were, likewise, similar between Dimebon- and placebo-treated patients.

As expected, the most frequently reported adverse events with the antihistamine were somnolence and dry mouth. A 5-mg treatment arm and another, large phase 3 safety study revealed consistent drug tolerability. For what it's worth, the phase 3 safety study showed that the drug can be taken with common AD medications, like cholinesterase inhibitors (eg, Aricept; Pfizer) or memantine (Namenda; Forest).

Results from the phase 3 efficacy study were to be used in conjunction with positive results from a phase 2 Russian study to support FDA approval. But, evidently, no more. 

In 2008, Pfizer agreed to pay Medivation $225 million upfront and another $500 million when the drug was approved. The agreement also conferred licensing rights to Pfizer for use of the drug in Huntington disease. Last month, results from a 90-day safety trial of Dimebon in HD showed that the drug may improve cognition.

The price of Medivation stock dropped nearly 30 points on release of the phase 3 trial results, from $40.12 to $12.88.

ADAS-cog = Alzheimer's Disease Assessment Scale-cognitive subscale; CIBIC-plus = Clinician's Interview-Based Impression of Change Plus Caregiver Input.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

Given the exclusion of Doug Bremner's plaintiff-funded PET study from Accutane litigation, specifically Palazzolo et al v Hoffman La Roche et al, the Emory psychiatrist (if he is still allowed to testify*) will need to rely on other clinical studies to convince a jury that Accutane causes depression and, in particular, suicidal depression. (For background on the trial's decision, go here and here.)

However, on this point, results from available clinical studies—none of which is well controlled—are mixed. And some data actually suggest an improvement in depression or anxiety with Accutane treatment.

So what are the data? The following is my review, based on several PubMed searches, of published clinical studies that attempted to assess any link between Accutane (or isotretinoin) use and depression or suicide. Overall I found 5 prospective, cohort studies in which patients received Accutane or a comparator treatment (eg, oral antibiotics), 4 prospective studies without comparator treatment, and 1 large retrospective population-based study. (Note: Case reports or case series are not included in this review.)

Prospective, cohort studies (treatments not randomized)

Ng et al, 2002 (University of Melbourne): Patients with acne (N = 215) received Accutane or antibiotic/topical treatments. No treatment-related differences were noted at 6 months in mean depression or quality-of-life scores, and there was no correlation between Accutane dose and depression score. However, 5 Accutane-treated patients (3%) withdrew from the study because of "worsening of mood." Financial support for the study is unclear.

Chia et al, 2005 (St. Louis University): Patients aged 12-19 years with moderate-severe acne (N = 132) received Accutane or conservative therapy (ie, oral or topical antibiotics or topical retinoid). Among the 101 subjects (77%) who completed the study, CES-D scores suggestive of clinically significant depression and rates of new-onset depression at 3 months were comparable in the 2 treatment groups. The authors found that improvement in acne with either treatment was associated with reduced depressive symptoms. Patients who were unavailable for follow-up did not have significantly different baseline depression scores, and dropout rates were comparable in the 2 treatment groups. The authors reported "None" to financial disclosures.

Bremner et al, 2005 (Emory University): Adults aged 18-50 years with "treatment-resistant" acne (N = 28) received Accutane or oral antibiotics. There were no significant increases in Hamilton depression scores at 4 months with either treatment and no significant between-treatment differences in these scores. Changes in "depression related to acne" were also not significantly different between the treatment groups. There was no correlation between baseline metabolism in the orbitofrontal cortex (an area of the brain implicated in depression), as determined by PET, and depression on any measure used in the study. The study was funded by Accutane plaintiffs (Liam Grant, 80%; Accutane-litigation lawyers, 20%).

Cohen et al, 2007 (University of Calgary): Patients aged 14 years or older with acne (N = 200) received Accutane or oral or topical antibiotics. At 2 months, there was no correlation between Accutane treatment and scores indicating the development of depression (CES-D or Zung Depression Status Inventory). The study was funded by the Centre for Advancement of Health, Calgary.

Kaymak et al, 2009 (University of Gazi): Patients with acne (N = 78) received Accutane or topical treatment. At 2 months, quality of life (measured by using the DLQI) was more impaired in the group receiving topical treatment. At 4 months, measures of quality of life, depression, and anxiety (the latter 2 via the BDI and HAD scale) showed improvement with Accutane treatment. Funding for the study is unclear.    

Prospective Accutane studies without comparator treatment

Rubinow et al, 1987: Patients with cystic acne (N = 72) were treated with 1 of 3 dosages of isotretinoin. The authors observed "significant reductions in anxiety." "[M]itigation of anxiety and depression [was] most robust in those patients with the greatest dermatologic improvement." Financial support of the study is unclear.

Strauss et al, 2001 (University of Iowa). Patients with severe recalcitrant nodular acne (N = 600) received either a micronized formulation of Accutane or standard Accutane treatment in double-blind fashion. At 20 weeks, the rates of adverse events were "generally lower" with the micronized formulation—specifically mucocutaneous events (eg, dry nose, dry eyes) and hypertriglyceridemia. Three patients taking the micronized drug and no patient taking the standard drug withdrew from the study because of depression. Psychiatric adverse events (eg, depression, anxiety, panic) were reported in 11 patients (4%) taking the micronized drug and 1 patient (0.3%) taking the standard formulation (who experienced a panic reaction). The study was funded by Roche. (N.B.—To my knowledge, the micronized formulation never made it to market.)

Ferahbas et al, 2004 (University of Ericyes, Turkey): Patients with "severe recalcitrant acne" (N = 45) received Accutane for 16 weeks. Among the 23 patients (51%) who completed the final assessment, the authors noted decreases in depression and anxiety scores (the latter being statistically significant) from baseline. No patient attempted or committed suicide. The abstract (I was not able to obtain a copy of the full article) does not provide information on the subjects who withdrew from the study. Funding for the study is also unclear.

Rehn et al, 2009 (Helsinki City Health Center): Male military conscripts (N = 135) received Accutane for 12 weeks. Among those who completed follow-up (93%), the mean depression score (via the BDI) and the proportion of patients with clinically significant depressive symptoms or suicidal ideation declined with treatment (the former, significantly). The authors, however, note that "one non-depressed patient attempted suicide while intoxicated with alcohol." It is assumed that the study was funded by the Finnish government, given the nature of the subjects.

Retrospective, population-based cohort study

Jick et al, 2000 (Boston Collaborative Drug Surveillance Program): By using the Canadian Saskatchewan Health Database and the UK General Practice Research Database, the authors analyzed computer-recorded histories from patients with acne who took Accutane (n = 7535) or oral antibiotics (n = 14,376). There was no increased risk of newly diagnosed depression or psychosis or attempted or committed suicide with Accutane exposure. This study, which was funded by Roche, has been criticized for its methodological limitations.

======================

Ten imperfect clinical studies, assessing the relationship between Accutane treatment and depression or suicide, were discovered. Two of these studies (the 2 largest) were funded by Roche, 1 study was funded by Accutane plaintiffs, and the other 7 studies were supported by independent or unclear sources. Overall these studies do not support an association between the available formulation of Accutane and depression or suicide; although Ng et al reported that 5 Accutane-treated patients (3%) dropped out of their study because of worsening mood, and 1 small study reported a high dropout rate for unclear reasons (Farahbas et al). Some studies indicate an improvement in mood with Accutane treatment, on the basis of an improvement in acne.

The prescribing information for Accutane, which is no longer sold by Roche in the United States, contains warnings regarding the risks of depression or suicide with treatment; although "[n]o mechanism of action has been established." On the basis of their study, Ng et al concluded that the potential risk of depression with Accutane treatment is "a rare unpredictable idiosyncratic side-effect."

BDI = Beck Depression Inventory; CES-D = Center for Epidemiologic Studies Depression scale; DLQI = Dermatology Life Quality Index; HAD = Hospital Anxiety and Depression; PET = positron emission tomography. 

* In the recent appellate ruling, the judge wrote, "We therefore remand this case to the trial judge to consider whether Dr. Bremner should be permitted to testify as an expert on general causation, without reference to the PET study. We leave to the judge's discretion whether to permit or require any further proceedings prior to issuing a decision on remand. We do not retain jurisdiction."

Photo of Roaccutane, aka Accutane, from Wikipedia.

The defunct Russian antihistamine Dimebon may (may) improve cognition in Huntington disease, according to newly published results of a short-term, but well-controlled, trial in the Archives of Neurology. However, the efficacy outcome—which was just 1 of 3 efficacy measures made in the trial—was not the primary endpoint of this company-sponsored phase 2 study of the drug's tolerability.

Among 91 ambulatory enrollees with HD,* 90-day treatment with Dimebon, 20 mg tid, significantly improved the mean score on the 30-point MMSE by less than 1 point (0.97; P = .03, vs placebo). No significant differences between Dimebon and placebo treatment were noted, however, on the Unified Huntington's Disease Rating Scale (which assesses motor function, as well as cognition) or the 13-item ADAS-cog. Tolerability of Dimebon, the primary outcome measure, was comparable to that of placebo: 87% and 82% of patients, respectively, completed treatment. No significant treatment differences were noted with regard to the most commonly reported adverse events (eg, falls, headache, and dizziness).

The rationale for studying Dimebon in HD and other neurodegenerative disorders, like Alzheimer disease, is based on the drug's ability in the laboratory to stabilize mitochondrial membranes and possibly promote neuronal stability or even regeneration. According to the study authors, "Abnormal mitochondrial depolarization, which can lead to collapse of the mitochondrial membrane and ultimately neuronal apoptosis, has been implicated in the pathophysiologic progression of HD and other neurodegenerative diseases."

A placebo-controlled study of Dimebon in AD revealed significant improvement in cognition, behavior, and general function at 6 and 12 months. Results of this study evidently motivated Pfizer to give Medivation $725 million in 2008 for worldwide marketing rights to the drug. Corporate-funded phase 3 studies of Dimebon are currently recruiting patients with HD (here) or AD (for instance, here or here).

News of the phase 2 results was associated with a bump in Medivation's share price (but not Pfizer's).

N.B.--Dimebon is the trade name for dimebolin HCl or latrepirdine.

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; MMSE = Mini-Mental State Examination.

* Study-eligible patients were allowed to take antipsychotic agents (at stable dosages), but they could not take cholinesterase inhibitors (eg, Aricept) or N-methyl-D-aspartate antagonists (eg, Namenda).

Image of Dimebon structure from Wikipedia.

Occupational exposure to the industrial solvent trichloroethylene increases the risk of Parkinson disease, according to researchers at the Parkinson's Institute and Clinical Center. The California-based, nonprofit organization released its study findings, which have not been presented at a scientific meeting or peer reviewed, on Sunday—apparently by way of press release. The data are scheduled to be presented at the annual meeting of the American Academy of Neurology in April.

According to sources picking up news of the study, data from 198 twin pairs in the World War II Veteran Twins Cohort Registry showed that the risk of PD in individuals with probable exposure to the solvent* was more than 5 times that of twins without probable exposure.** In a MedPage Today piece, an odds ratio (5.5) is reported, but no frequency rates of disease are provided. Also the 95% confidence interval for the odds ratio is very wide (1.02, 30)—indicating that the accuracy of the measured risk is uncertain.

Interest in trichloroethylene exposure as a risk factor in PD extends back to the early 90s, when it was reported by German investigators that a metabolite of the solvent is chemically similar to the neurotoxin MPTP. (The metabolite of MPTP, MPP+, has a predilection for the dopamine-producing neurons of the substantia nigra—the area of the brain that is primarily affected in PD. The MPTP story, itself, is fascinating and the subject of an excellent Nova episode, "The Case of the Frozen Addict," from 1986.)

In 2008, researchers at the University of Kentucky published their study of 30 industrial workers with PD or parkinsonism, who had long-term exposure to trichloroethylene. The study authors suggested that a worker's proximity to the solvent was related to his risk of the movement disorder. These findings were complemented by animal studies, which showed that oral intake of trichloroethylene for 6 weeks resulted in the degeneration of brain areas that are typically affected in PD.

* Presumed on the basis of occupation (eg, aircraft mechanic, electrician).

** The study of twins (and presumably, these are identical twins) largely eliminates any potentially confounding genetic risks of Parkinson disease.

Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers at Wikimedia Commons.

It's one thing for a physician to serve as a medical expert for plaintiffs in court cases. It's very much another when plaintiffs actually commission a physician to conduct a study—the results of which are intended to support their litigation. (Think Andrew Wakefield and the associated antivaccination mess.)

Now, according to a newly released court opinion (courtesy of Jim Beck at the Drug and Device Law blog), it is revealed that plaintiffs in the Accutane litigation* specifically commissioned Emory psychiatrist J. Douglas Bremner to conduct a PET study, which led to the conclusion that Accutane reduces metabolism in "a brain area known to mediate symptoms of depression." The results of the uncontrolled study were published in a 2005 issue of the peer-reviewed American Journal of Psychiatry,** and for the purposes of the court case, "Bremner issued an expert report opining that Accutane can cause depression and suicide."

If this conflict of interest isn't sufficiently disturbing, the court opinion reveals further that Bremner's commissioned data were highly suspect.

During a lengthy pretrial hearing, in which Bremner was questioned about the PET study by defendant's counsel,

Bremner was repeatedly confronted with problems in the PET study, including missing data, inaccurate data, and deviations from the methodology he claimed to have followed. As a result...the court permitted Bremner to re-work his study data and issue a supplemental expert report and allowed defendant to re-depose him. When the hearing resumed, Bremner admitted that certain underlying data, known as "Bmax numbers" which had been used to make critical calculations in the study, [were] not retrievable from its computerized format, and some of the data concerning individual study subjects [were] still inaccurate.

(I could be wrong here, but Bmax, in this context, appears to be a maximum basal metabolic rate of the brain area in question—a necessary reference standard from which to calculate any metabolic changes.)

The opinion goes on to state,

[T]hat Bremner did not actually use the methodology he claimed to have used. Although his PET scan article was peer-reviewed, he admitted that he did not in fact follow the steps described in the article. 

Significantly, contrary to representation made in the article, [Bremner] did not get before-and-after Skindex questionnaires from many of the subjects. Those questionnaires were designed to elicit the extent to which the subjects might be worried about their acne. This was relevant because some scientists were of the view that worrying, as well as depression, could affect activity in the orbital frontal cortex.

Note: The orbitofrontal cortex is the brain area in question. Reduced volume of the orbitofrontal cortex has been implicated in major depressive disorder. According to Bremner's published article, the Skindex questionnaire was "administered before and after treatment." The implication is that it was administered to all participating subjects.

The opinion continues,

Bremner also could not document much of the data on which his published results were based. Further, he admitted that some of the statistical analysis was inaccurate. For example, in the October 2, 2006 hearing session, Bremner admitted that, for each study participant, comparing the activity in the orbital frontal cortex with the activity in the whole brain revealed no difference between the subject who took Accutane and those who took antibiotics.

Retreating from the results claimed in his 2005 article, he testified at the hearing that the "absolute metabolic rates" for the two groups was significantly different, and contended that was the key finding of the PET study. However, Bremner claimed that he could not produce the source data for that analysis because the "Bmax" numbers used to calculate those metabolic rates was on an optical computer drive that could not be opened.

Further, while he admitted that some of the Bmax numbers he used in his calculations were inaccurate, he could not check the accuracy of the remaining numbers because the original data could not be retrieved.

An expert's scientific peers cannot fairly judge the expert's written work, including whether it is worthy of publication, if his article does not accurately represent either the underlying data or what the author did to produce his results. We agree with the trial judge that, in essence, Bremner's study was not "soundly and reliably generated."

While this information indicates that Bremner and his coauthors should have retracted the PET study from publication in the AJP, the shaken peer-review process is sustained by a mere notice of correction. At the end of the Letters to the Editor section in a 2008 issue of the AJP is this short paragraph in reduced type:

Corrections

In the article "Functional Brain Imaging Alterations in Acne Patients Treated With Isotretinoin," by J. Douglas Bremner et al. (Am J Psychiatry 2005; 162:983-991), only seven subjects in each treatment group completed the Skindex posttreatment. The secondary analysis that included whole brain metabolism before and after treatment did not reach significance on re-analysis.

In the meantime, the authors of at least 42 articles, according to a Google search, have cited Bremner's PET study. These authors include Bremner himself, who wrote in 2008, "Administration of [Accutane] (but not antibiotic) was associated with a 16% decrease in brain metabolism in the orbitofrontal cortex after four months of treatment."

Also a blogger, Bremner, in an ironic turn, charged conflicts of interest among Roche's key opinion leaders who believe that Accutane does not cause depression.

PET = positron emission tomography. 

* Specifically Palazzolo v Hoffman-LaRoche, in which a mother argued that Accutane caused the suicide of her teenage son. Since July 2009, Roche's trade name for the drug is Roaccutane.

** Published disclosures do reveal that the PET study was "[s]upported by funding from Liam Grant, director of the Roaccutane Action Group (80%), and by lawyers involved in Accutane litigation (20%)." The amount of money that Grant provided is not clear; however, information provided by Bremner here indicates that Grant, whose son committed suicide while taking Accutane, contacted Bremner directly and gave an "unrestricted grant" to Emory for the PET study. A 2005 article in USA Today indicates that Grant spent about $1 million to fund the Emory PET study and a rodent study at the University of Massachusetts.

Unrelated, generic PET image from Wikipedia.

02/06/10 addendum: At his blog, Bremner responded today to Jim Beck's post and this post. Bremner harshly and wrongly, in my opinion, describes our discussions of the court opinion as "an outpouring of hate." (I think "criticism" is a better descriptor.) He also casts aspersions at Beck's and my respective alliances with the pharmaceutical industry. (Beck makes it no secret that he represents drug companies in related litigation. I make it no secret that I have worked in pharmaceutical marketing.* While this information is important to know, it doesn't make our criticisms or concerns about plaintiff-sponsored research necessarily baseless.)

Bremner continues by denying that his PET study was "commissioned for the litigation," despite the fact that the court opinion states, on page 3, "There is no dispute that the study was commissioned specifically for use in this litigation." This statement clearly indicates that opposing parties in the litigation did not contest this point, despite the fact that Bremner disagrees with it.

Bremner then fails to support his disagreement. He merely affirms that 80% of the PET study was funded by an Accutane plaintiff (Liam Grant) and writes that Roche wouldn't perform a study (presumably a PET study) or supply medication for a study. Bremner's allegation that Roche wouldn't participate in an Accutane-PET study hardly refutes the statement that Bremner's PET study was commissioned by the plaintiffs. And the fact that the drug industry supports a lot of clinical research, much of it under FDA scrutiny as Jim Beck stresses, doesn't mean that a) a physician is justified in accepting plaintiff money to perform research (whether intended for use in their litigation); b) a physician who accepts plaintiff money for research is immune to plaintiff bias; or c) accepting plaintiff money somehow makes up for any potential bias in pharma-funded research.

Bremner then addresses the study's missing data (which he says were erroneously labeled "Bmax" by the court). According to Bremner, these data were eventually retrieved, albeit after "a court deadline had passed"; however, Bremner does not address the court's disturbing statement, "some of the data concerning individual study subjects [were] still inaccurate."

Bremner minimizes the court's allegation that he did not follow the study's described methodology with respect to the use of the Skindex questionnaire, by stating that "[i]t was by no means the primary outcome of the study" and that "there was no correlation between this item and brain function." He alleges that the questionnaire was added "late" to the study protocol at the request of a "dermatologist who was later found to be a paid consultant to Roche." The implication is that Roche, through this dermatologist, somehow tried to manipulate Bremner's PET study. (It should be noted that the authors of the study do not include a dermatologist, as far as I can tell; so if a dermatologist had significant input into the study protocol, this should have been revealed in the study article.) 

The Skindex questionnaire (if a PubMed search is any indication) appears to be a widely used, quality-of-life measure in dermatologic studies. The court wrote that the consistent use of the Skindex questionnaire "was relevant because some scientists were of the view that worrying, as well as depression, could affect activity in the orbital frontal cortex." The article by Bremner et al indicates that the Skindex questionnaire was 1 of 3 components of the study's behavioral assessment (the other 2 being the Hamilton Depression Rating Scale and a clinician-administered acne questionnaire).

In any event, Bremner et al wrote that the Skindex questionnaire was "administered before and after treatment" in his 28-person PET study. This information, it turns out, was misleading, if not outrightly false. The questionnaire was administered to only half of the enrollees before and after treatment, according to the 2008 correction.

Bremner does acknowledge that "some data entry errors were found" in his study but that a "re-analysis of the study resulted in no change in the conclusion." This latter statement doesn't appear to be entirely true, at least according to the court opinion and to the 2008 correction.

In their 2005 AJP article, Bremner et al wrote,

Administration of [Accutane] but not antibiotic was associated with decreased brain metabolism in the orbitofrontal cortex after 4 months of treatment...This effect was seen for both absolute metabolism...and for the ratio of orbitofrontal to whole brain metabolism (F=4.64, df=1, 110, p<0.05). A secondary analysis included pretreatment whole brain metabolism in the model and also showed greater reductions in orbitofrontal metabolism after treatment in the isotretinoin group than in the antibiotic group (F=9.66, df=1, 104, p=0.002). 

But the court wrote,

[I]n the October 2, 2006 hearing session, Bremner admitted that, for each study participant, comparing the activity in the orbital frontal cortex with the activity in the whole brain revealed no difference between the subject who took Accutane and those who took antibiotics.

And the 2008 correction states,

The secondary analysis that included whole brain metabolism before and after treatment did not reach significance on re-analysis.

Bremner concludes his rebuttal by stating that "it doesn't matter" and provides a link to a 2008 review article he cowrote. In this article, Bremner proposes how retinoids (like Accutane) may be involved in the neurobiology of affective disorders and cites 2 suggestive mice studies. Among the clinical studies described by Bremner, none of which is well-controlled, the results are mixed. Some suggest a link between Accutane use and depression, and others do not.

I have no vested interest in whether Accutane causes depression or suicide; however, the data, as they currently exist and as Bremner presents them, are not abundantly compelling.** Furthermore, I maintain that plaintiff-sponsored research is disturbing and represents a potentially significant conflict of interest for the investigator who accepts plaintiff funds to perform related studies—particularly studies that may be used to the advantage of the plaintiff in ongoing litigation.

Whether the results of Bremner's PET study, which the court found problematic, are valid can only be determined by their reproducibility—ideally in a randomized, double-blind trial. 

* However, during the last 6 years, I've worked in continuing medical education (CME); during the last 2 years, this has been in a freelance capacity. I'm most certainly not paid by anyone to blog.

** Which is why plaintiffs are interested in funding research.

Raising a host of questions, from practical to philosophical, English and Belgian investigators showed that some patients with profound disorders of consciousness may be able to communicate—albeit in rudimentary fashion and with the aid of a million-dollar machine. Their functional MRI study of patients in persistent vegetative or "minimally conscious" state is available online today at the NEJM web site.

Among 54 severely disabled patients, investigators found that 5 could "willfully modulate their brain activity," as seen on fMRI pictures, in response to suggested motor imagery. Specifically when these patients were asked to imagine playing tennis, parts of the supplementary motor area reliably lit up. Four of the 5 patients could also respond to suggested spatial imagery, like navigating through a familiar city, by activating the parahippocampal gyrus. Follow-up bedside testing showed "some sign of awareness" in 3 of the 5 patients—suggesting that voluntary behavioral cues were missed before the fMRI assessment or that fMRI training primed these patients to respond behaviorally at the bedside (the former seems more likely).

The investigators then selected 1 patient with reliable fMRI responses to undergo training that correlated the motor imagery with "yes" and the spatial imagery with "no." The patient was then able to use the technique during fMRI to accurately answer yes-no questions, like Is your father's name Alexander? However, back at the bedside, no form of communication could be established with this patient.

All 5 responsive patients had traumatic brain injury without anoxic damage (among 32 in the study population). It is important to note that none of the 16 patients with anoxic brain injury responded (a fact that editorialist Allan Ropper also stresses).* Before fMRI testing, 4 of the responsive patients were diagnosed with vegetative state, including the patient who underwent communication training.

The American Academy of Neurology, the flagship organization for practicing US neurologists, provides the following criteria for the diagnosis of vegetative state:

• No evidence of awareness of self or environment and an inability to interact with others
• No evidence of sustained, reproducible, purposeful, or voluntary behavioral responses to visual, auditory, tactile, or noxious stimuli
• No evidence of language comprehension or expression
• Intermittent wakefulness manifested by the presence of sleep-wake cycles
• Sufficiently preserved hypothalamic and brainstem autonomic functions to permit survival with medical and nursing care
• Bowel and bladder incontinence
• Variably preserved cranial nerve and spinal reflexes

Minimally conscious state, which acknowledges the intermediate stage between no and some awareness in the severely brain damaged, is defined as follows:

A condition of severely altered consciousness in which minimal but definite behavioral evidence of self or environmental awareness is demonstrated.

Diagnosis: limited but clearly discernible self or environmental awareness on a reproducible or sustained basis by demonstrating one or more behaviors, including, following simple commands, gesturing yes/no answers to questions, intelligible verbalizations, purposeful behavior, appropriate smiling or crying, reaching for and touching objects, and pursuit eye movements.

Course: may be a transient stage in the recovery after severe head injury or other brain insult or a permanent condition.

Medicolegal cases of Jobes (1987) and Wendland (2002).

Results of this fMRI study suggest that the imaging technique might be useful for distinguishing the 2 conditions (and that, perhaps, the definition of minimally conscious state should include fMRI-dependent findings) and for establishing communication in patients with reproducible fMRI responses.

* Ropper also concludes his NEJM editorial with a groan-inducing pun that should not be reproduced.

Image of Berkeley's fMRI machine from Wikipedia.

In the neck-and-neck race to market the first-ever disease-modifying pill for multiple sclerosis, both Novartis and Merck Serono scored by getting their respective pivotal trials of fingolimod and cladribine published in the venerable NEJM this week. (For background, start at last year's No. 8 story.)

And because I like to make comparative tables, here's another one providing the salient features of the 3 studies—all of which enrolled patients with relapsing-remitting MS.

Study Features	FREEDOMS	TRANSFORMS	CLARITY
Phase	3	2	3
Drug	Fingolimod 0.5 or 1.25 mg/d	Fingolimod 0.5 or 1.25 mg/d	Cladribine 3.5 or 5.25 mg/kg*
Comparator drug	Placebo	IM interferon-beta 1a 30 µg/wk	Placebo
Duration	24 months	12 months	96 weeks
Enrollees	1272	1292	1326
Completers	1033 (81%)	1153 (89%)	1184 (89%)
Annualized relapse rate (primary outcome)	55% or 60% ↓	39% or 51% ↓	54% or 58% ↓
Major secondary outcomes	26% or 31% ↓ disability progression; significant ↓ MRI lesions	No difference in disability progression	~30% higher relapse-free rate; significantly ↓ 3-month disability progression and MRI lesion burden
Notable drug-related adverse events	Bradycardia, AV block, macular edema, high liver enzymes, mild HTN	Fatal infections,** nonfatal herpes, bradycardia, AV block, HTN, macular edema, skin cancer, high liver enzymes	Lymphocytopenia, herpes zoster

* 2-4 "short" courses for the first 48 weeks, then 2 short courses starting at weeks 48 and 52 (total treatment, 8-20 days/year).
** Two in high-dose group: disseminated primary varicella zoster and herpes encephalitis.

What's the take-home?

Although trial-to-trial comparisons are problematic, both drugs appear to have comparable and significant efficacy. Novartis, developer of fingolimod, has an edge owing to its phase 2 study with the standard MS treatment of interferon beta.

But the uptake of these drugs, once they are approved (and I predict they will be...eventually), will likely depend on their safety profiles. Fingolimod, in particular, is associated with some wicked side effects.

AV = atrioventricular; CLARITY = Cladribine Tablets Treating Multiple Sclerosis Orally; FREEDOMS = FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; HTN = hypertension; TRANSFORMS = Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis.

This is the final post in which randomized, clinical trials of the potentially active ingredients in the branded drink Souvenaid are reviewed. (For background on Souvenaid's development, go here, here, here, and here.) 

The remaining components to be examined in the nutritional supplement are phospholipids, choline, and uridine monophosphate (UMP).

In the case of UMP, a directed PubMed search reveals no randomized, controlled trial of the RNA nucleotide in Alzheimer disease. Therefore the rationale for assessing UMP in cognitive dysfunction appears to extend solely from animal studies (for instance, see a 2008 rat study by anchor author Wurtman, who is also coauthor of the recently published Souvenaid study).

The rationales for giving phospholipids or choline to AD patients are either 1) to bolster the integrity of neuronal membranes by providing the necessary building blocks, or b) in the case of choline, to supply a precursor for the neurotransmitter acetylcholine, which is deficient in AD. 

Barring the negative studies of lecithin,* a potential source of both phospholipids and choline, there are at least 9 randomized, controlled trials (published from 1986 to 2003) of these substances in dementia. Six studies, from the 80s and 90s, assessed the specific phospholipid phosphatidylserine; 3 studies assessed choline alfoscerate or citicoline. Most of these studies enrolled outpatients with mild-to-moderate AD. General study features are tabulated here:

Intervention	N	Duration	Outcome in a Nutshell
Phosphatidylserine
1986	42	6 wk	Trend toward improvement or significantly improved
1986	No abstract	—	—
1992	51	3 mo	Improvement observed in milder disease
1992	33	2 mo	Mixed improvement
1992**	40	6 mo	PET-correlated cognitive improvement
1994**	70	6 mo	Temporary improvement
Acetylcholine precursors
1993	126	?	Significant improvements with choline alfoscerate
1999	30	3 mo	Citicoline associated with improvements in APOE ε4 carriers; effect more pronounced in mild disease and associated with physiologic changes
2003	261	6 mo	Choline alfoscerate improved cognition or delayed cognitive decline

Cumulative data from the relatively small, controlled studies of phosphatidylserine in AD suggest that whatever cognitive improvements exist, they are short lived.

The most compelling support for the use of choline (ie, choline alfoscerate) comes from a sizeable, randomized, placebo-controlled, 6-month study performed at the Instituto Nacional de la Senectud in Mexico City. Cognitive assessments, performed with the ADAS-cog and other well-recognized tests, showed either a significant delay in cognitive decline or actual cognitive improvement. 

Nevertheless, these impressive results must be replicated. 

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; PET = positron emission tomography.

* A directed PubMed search reveals at least 5 studies of lecithin in AD, published from 1981 to 1987. Among the 3 small placebo-controlled studies in which an abstract is provided, none showed clinical improvement with supplementation (treatment duration, from 10 weeks to 6 months), despite a rise in plasma choline levels. These search results omit at least 8 trials of the defunct cholinesterase inhibitor tacrine, in which lecithin was provided as standard treatment.

** Treatment options were phosphatidylserine or pyritinol, a vitamin B6 analog.

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.